DE2337047A1 - NEW CEPHALOSPORIN COMPOUNDS AND PROCEDURES FOR THEIR PRODUCTION - Google Patents

Description

Glaxo Laboratories Limited, Greenford, Middlesex / England

Novel cephalosporin compounds and processes for their preparation

The invention relates to a process for converting cephalosporin compounds and the products obtained thereby.

The availability of cephalosporin compounds from penicillin compounds by ring expansion processes and the preparation of 3-halomethylcephalosporins by halogenation of such Ring-expanded products has generated interest in processes for converting 3-halomethylcephalosporins into to develop related compounds containing other substituted methyl groups at the 3-position.

One method that has been used in such conversions is the replacement of the halogen atom with nucleophiles, being various carbon, nitrogen, oxygen and Sulfur nucleophiles can be used.This method is described, for example, in British patent specification 1,241,657 and in Belgian patent 755 256.

It has now been found that a particular group of carbon nucleophiles with certain 3-halomethyl- and 3-halo- (subst.-methyl) -cephalosporins can be implemented, with

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man.related cephalosporins, which have an ethyl or contain substituted ethyl group in the 3-position. In particular it was found that a cephalosporin compound which in the 3-position is the skeletal group

3 - C - X

contains, in which X is a halogen atom, for example a chlorine, bromine or iodine atom, and which does not contain any free amino or carboxyl group (such compounds are hereinafter generally referred to as "3-halomethylcephalosporins"), with the metal salt one weak carbon acid, ie one which (determined estimated for a dilute aqueous solution at 25 ⁰ C in or) a pKa value has, which is not less than 13. This is a 3-ethyl or 3- (obtained subst .-Ethyl) -cephalosporin.

The method according to the invention finds particular application the production of 3-ethylcephalosporins, which are used in the Belgian Patent 770,989 by the same applicant are.

Suitable carbon acid salts,

which can be formed in situ if desired include those of the formula

C- R

R ³

(D

M means a metal tone with the value η and that be the same or different

12th

R, R and R

can, each be a hydrogen atom or an organic group

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12 3 mean or wherein two or more of the groups R, R and R together form a divalent or trivalent function and / or are bonded together in such a way that they, together with the carbon atom, to which they are attached form a cyclic structure, with any of the remaining groups R, R and R ^ represent a hydrogen atom or an organic group

12 ^ means. Organic groups R, R and R- 'can be carbon, Contain oxygen, sulfur, nitrogen and phosphorus atoms, and they will generally contain 1 to 30 such atoms. If desired, these groups may contain substituents, although it should be noted that substituents how chlorine, bromine and iodine atoms can cause competitive reactions.

The metal atom M is advantageously a monovalent or divalent one Metal and it is preferably an alkali metal atom, for example lithium, sodium or potassium. It was found, that the use of the lithium salts is particularly expedient. Other metals that can be used include magnesium, Cadmium and zinc.

12 ^ If any of the groups R, R and R- ^ organic groups are, these can be, for example, alkyl, for example with 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, η-butyl, etc .; Alkenyl, for example having 2 to 8 carbon atoms such as vinyl, propenyl, butenyl, etc .; al ^ .cyclic Groups, for example with 3 to 7 membered rings such as Cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentadienyl, etc .; Aryl, for example phenyl or naphthyl, or aralkyl, for example those in which the aryl group is phenyl or naphthyl and the alkyl portion is 1 to 4 carbon contains atoms such as benzyl or phenethyl.

Any two of the groups R ¹ , R ² and R ⁵ , together with the bonded carbon atom, can have cyclic structures such as, for example, 5- or 6-membered carbocyclic rings, for example cyclopentyl or cyclohexyl, and 5- or 6-membered

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ge heterocyclic structures that have one or more heteroatoms such as oxygen, sulfur, nitrogen and Phosphorus atoms such as in dithianyl and dithiolanyl rings or form the corresponding sulfoxides. Alternatively, all three groups R, R and R- ^ together with the attached Carbon atom form a cyclic structure such as a phenyl group.

Similarly, two of the groups mentioned together can form a divalent Function, for example an alkylene group such as methylene, form.

The cephalosporin compounds that can be obtained by converting a carbonic acid sal2ffider Formula I with a 3-halomethylcephalosporin are characterized in that they are the basic group in the 3-position

-C-C-R ^

1 2
L, where R, R and

own.

t 13

12 >
contain, in which R, R and R are as defined above

The reaction is preferably carried out in an inert solvent, advantageously a polar organic liquid such as an aliphatic or cyclic ether, for example diethyl ether, tetrahydrofuran or dimethoxyethane, or an amide solvent, for example dimethylformamide or hexamethylphosphorotriamide, or in a mixture of such compounds. The 3-Halogenmethylcephalosporin v is optionally prepared zv / eckdienlich as a solid or in ^ dissolution to a Lö _SU ng of the salt of carbonic acid zugefügt.Das carbon acid salt can be prepared in situ by reaction with another carbon acid salt / erden.Beispielsweise can be 1,3-dithianyl Form lithium by reacting 1,3-dithiane with n-butyllithium. It is necessary to keep moisture and oxygen out of the reaction system and use dried solvents and the reaction

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under an atmosphere of, for example, oxygen-free nitrogen, helium or argon. Salt is expediently used in an amount equivalent to "the 3-halomethylcephalosporin or in excess, for example up to 10 times the stoichiometrically equivalent Lot. The conversion can be monitored or followed, for example by thin layer chromatography.

In general should low reaction temperatures ranging from -150 to +30 ⁰ C used, temperatures from -100 to -10 ⁰ C are preferred. '

It has been found that implementation can be accelerated by using them. performs in the presence of a transition metal, which forms an "ate" complex with the carbonic acid salt. Suitable transition metals for this purpose include copper, iron, cobalt and manganese in the form of copper (I), iron (II), Cobalt (II) and manganese (II) salts. These salts become useful to the solution of the carbonic acid salt before the 3-halomethylcephalosporin added so that the "ate" complex can form. Compounds such as trialkylphosphines, which are used as Serving source of ligands can also be added in certain cases, for example to the transition metal to solubilize and stabilize the "ate" complex.

The desired products can after hydrolysis, for example with saturated aqueous ammonium chloride, after oxidation, for example with oxygen or a copper (II) salt, and subsequent hydrolysis or after the alkylation, for example with methyl iodide, and subsequent hydrolysis the reaction mixture can be isolated.

As stated above, the 3-halomethylcephalosporins used as starting material should not contain any free amino or Contain carboxyl groups. Suitable cephalosporins that can be used as starting materials correspond to formula

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COOR

(ID

R ^{a is} a protected amino group,

b
R is a carboxyl protecting or blocking group,

for example the remainder of an ester-forming alcohol, phenol, silanol or stannanol R OH,

CD
R and R, which may be the same or different

can, one hydrogen atom or one organic group, Z> S or> S = 0 (α or ß), X mean halogen (chlorine, bromine or iodine) and the dashed lines between the 2-, 3 and 4-

2 ^ positions indicate that the compound is a ^ - or Δ cepheraisomer or a mixture thereof.

The product obtained by reacting such a cephalosporin with a carbonic acid salt of the formula I can by the formula

COOR

(III)

in which the various symbols have the definitions given above.

It should be noted that the basic formulas or skeletal formulas II and III also include compounds which structurally are not directly included, for example 2-substituted cephalosporins such as 2-methylcephalosporins, 2-Me-

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ethylene and 2, a-dimethyl- ^ -cephalosporins and 7 α-substituted Cephalosporins.

In the compounds of the formula Ii, X is preferably bromine. The compounds of the formulas II and III are preferably Ceph-3-em derivatives, and Z denotes a sulfoxide group, then this has prefers the ß-configuration.

The 3-halomethylcephalo-

approx
Sporins of the formula II, in which R and R are each hydrogen, can be prepared by bromination of the corresponding 3- (unsubst.-methyl) -cephalosporins using, for example, N-bromimide such as N-bromosuccinimide, if desired with subsequent halogen exchange to obtain a chlorine - or to introduce iodine atom. Such halogenation reactions are described in the above-mentioned British patent specification 1,241,657 and in Belgian patent specification 755,256 of the same applicant

»C / d

described. Compounds of the formula II in which R and / or R are organic groups can be obtained by bromination of a suitable 3- (subst.-methyl) -cephalosporins produced v / ground, again with subsequent halogen exchange, if desired will; Halogenations of this type are described in the German patent (Patent application P

with the case no. Cephalosporin 165 of the same applicant corresponding to British note 34296/72, which is filed on the same day as the present application). In the above formulas II and III, R ^a conveniently denotes an acylamido group, for example one containing 1 to 20 carbon atoms, especially that of a penicillin obtained by fermentation processes, for example a phenylacetamido or phenoxyacetamido group, since compounds of the formula II easily pass through Ring expansion reactions can be produced from such penicillins. The group R ^a can also contain a formamido group. This group is essentially stable under the reaction conditions and it can easily be cleaved afterwards, whereby another acyl group can be introduced.

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It may happen that the acylamido group is not the desired group in the final product. However, this can be changed by subsequent conversions as described below. It is not necessary that an acylamido group R ^a in a compound of the formula II is completely inert to the reaction conditions, since it can be cleaved in such subsequent conversions.

The carboxyl protecting group R or the carboxyl blocking group R in Formulas II and III above are useful

Esterification groups associated with an alcohol (aliphatic or araliphatic), with a phenol, silanol, stannanol or, with an acid that are easily formed with a can be split off at a later stage of the implementation. If an alcohol, phenol, silanol or stannanol is used to esterify the Carboxyl group is used, this compound preferably contains not more than 20 carbon atoms.

c d If either or both of the groups R and R are in the Formulas II and III are organic groups, these are preferably carbon groups containing 1 to 20 carbon atoms and desirably do not have any ethylenic or acetylenic unsaturation. Suitable Groups thus include, for example, lower alkyl groups such as methyl, ethyl or propyl, aryl-lower alkyl groups such as benzyl and aryl groups such as phenyl.

When the product of formula III is a 7β-acylamido compound which does not contain the desired acyl group, the 7β-acylamido compound can be N-deacylated, whereby the corresponding 7β-amino compound is obtained, and the latter can be acylated with a suitable acylating agent.

Suitable processes for the N-deacylation of cephalosporin derivatives, which contain 7β-acylamido groups are, for example, in British patents 1,041,985, 1,119,806, 1,227,014, 1,239,814, 1,244,191 and 1,241,655. A

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another method of N-deacylation that can be used can is acid catalysis. You can do that for example. «Ine N-deformylation of a 7ß-formamido group with the help of a Perform mineral acid, as described in British patent specification 1 290 327, or with the help of a Lewis acid, as described in British Patent 1,321,265 is.

Alternatively, one can use enzymic N-entacyiation processes use instead of chemical processes.

The 7β-araino compound can be used as an insoluble salt, for example as hydrochloride or as hydrogen p-toluenesulfonate, separated or it can be precipitated by adjusting the pH (e.g. to an isoelectric point) and if necessary it can be extracted with a suitable solvent can be isolated. The 7β-amino compound can then be acylated again. The re-acylation can be done with the acylating agent of choice. A wide variety of acylating agents based on the Cephalosporin can be used is already described in the literature.

If the 7ß-acylamido group contains an amino group, it will this may be necessary during the various reaction stages to protect. The protecting group is conveniently a group which can be removed by hydrolysis without affecting the remainder of the molecule is attacked, in particular without the lactam and 7β-amido bonds being attacked. The amino protecting group and the esterification group at the 4-C00H position can be removed with the same reagent. A an advantageous method is to remove both groups at the last stage in the preparative sequence. Protected amine groups include urethane, arylmethyl (e.g. trityl) amino, or sulfenylamineq types. Such Groups can generally with one or more reagents such as with dilute mineral acids, for example

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with dilute hydrochloric acid, concentrated organic acids, for example concentrated acetic acid, trifluoroacetic acid and liquid hydrogen bromide at very low temperatures, for example at -80 ⁰ C, are removed. A suitable protecting group is the t-butoxycarbonyl group, which can easily be removed by hydrolysis with dilute mineral acid, for example dilute hydrochloric acid, or preferably with a strong organic acid (for example formic acid or trifluoroacetic acid), for example at a temperature of 0 to .40 ⁰ C, preferably at room temperature, (15 to 25 ° C), is removed. Another useful protecting group is. the 2,2,2-trichloroethoxycarbonyl group, which can be removed with a reagent such as zinc / acetic acid, zinc / formic acid, zinc / lower alcohols, or zinc / pyridine.

If the product of the formula III is a sulfide, this can, if desired, be converted into the corresponding sulfoxide v / ground, for example as described by Cocker et al (J. Chem. Soc. 1965, 5015). The cephalosporin compound (III) may be mixed with the oxidizing agent in an amount such that approximately 1 atom of active oxygen / atom of dihydrothiazine sulfur is available. The oxidizing agent should preferably be an oxidizing agent which favors formation des 1ß-Oxyds or that results in a mixture of 1a and 1ß-oxides, in which the 1ß-Oxyds predominates. Suitable oxidizing agents include metaperiodic acid, peracetic acid, permonophthalic acid and m-chloroperbenzoic acid. One should be careful and avoid an excess of oxidizing agent, as this could cause the formation of 1,1-dioxide.

Since ·; "1-oxide is preferably formed at a temperature below +10 ⁰ C, to minimize the amount sulfone.

If the product of the formula III is a sulfoxide, this can be converted into the corresponding sulfide in a similar manner, for example by reducing the corresponding acyloxysulfonium or

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Alkyloxysulfonlumsalzes take place, which is prepared in situ by reaction with, for example, acetyl chloride in the case of an acetoxysulfonium salt, the reduction, for example, with sodium dithionite or with iodide ions such as in a solution of potassium iodide in a water-miscible solvent, for example acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out at a temperature of -20 to +50 ⁰ C.

Alternatively, the reduction of the phosphorus trichloride or tribromide in Sulfoxydgruppe with solvents such as methylene chloride, dimethylformamide or tetrahydrofuran, preferably at a temperature of -20 to +50 ⁰ C, take place.

Ceph-2-em compounds of the formula III can if desired converted into the corresponding Ceph-3-em-compound, for example by oxidation of the corresponding Ceph-3-em ~ 1-oxide as described for example in the published Dutch patent application 6910830, and then there is a reduction of the sulfoxide group, for example with the methods described above.

The group R ^a in the formula of the initial and final products can mean a wide variety of acylamido groups, depending on the Yfunsch.

Specific acyl groups which ^{may appear as acylamido groups R a} are given in the following exemplary list.

(i) ^RUc _n ^H 2 _n ^C0 "» where R ^{u is} aryl (carbocyclic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, cycloalkadienyl or a non-aromatic or mesoionic group and η is an integer from 1 to 4. Examples for these groups include phenylacetyl; substituted phenylacetyl, for example fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl,

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Methoxyphenylacetyl, methylphenylacetyl or hydroxyphenylacetyl; N, N-bis (2-chloroethyl) aminophenylpropionyl; Thien-2- and -3-ylacetyl; 4-isoxazolyl and substituted 4-isoxazolylacetyl; Pyridylacetyl; Tetrazolylacetyl; Cyclohexadienyl or a sydnonacetyl group.-The substituted 4-isoxazolyl group can be a J-aryl-S-methyl-isoxazol ^ -yl group be. The aryl group can be, for example, a phenyl or halophenyl group, for example chlorine or Bromophenyl. An acyl group of this type is 3-o-chlorophenyl-5-methylisoxazol-4-yl-acetyl.

(ii) ^c _n ^H 2n + 1 ^C0 "» where η is an integer from 1 to 7. The alkyl group can be straight-chain or branched and, if desired, be interrupted by an oxygen or sulfur atom or, for example, by a cyano group, a carboxy group, a Alkoxycarbonyl group, a hydroxy group or a carboxycarbonyl group (-CO.COOH), Examples of such groups include cyanoacetyl, hexanoyl, heptanoyl, octanoyl and butylthioacetyl.

(iii) ^c _n ^H 2n-1 ^C0 ~ '' ^where ^ ^{in n is} an integer from 2 to 7. The alkenyl group can be straight-chain or branched and, if desired, be interrupted by an oxygen or a sulfur atom. An example of such a group is allylthioacetyl.

R ^V
(iv) R ^U OC-CO-, where R ^{u is} the given in (i)

R ^w

has meaning and can also mean benzyl and R ^v and R, which can be the same or different, each mean hydrogen, phenyl, benzyl, phenethyl or lower-alkyl. Examples of such groups are phenoxyacetyl, 2-phenoxy-2-phenylacetyl, phenoxypropionyl, 2-phenoxybutyryl, benzyloxycarbonyl, 2-phenoxypropionyl, 2-phenoxybutyryl, methylthiophenoxyacetyl.

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R ^V
(ν) R ^U SC-CO-, where R ^{u is} the de- given in (i)

¹ w

R ^w

has finition and can also mean benzyl and R ^v and R ^{w have} the definitions given in (iv). Examples of such groups include S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl.

(vi) R ^u Z (CH ₂ ) _m C0-, where R ^{u has} the definition given in (i) and can additionally be benzyl, Z is an oxygen or sulfur atom and m is an integer from 2 to 5. An example of such a group is S-benzylthiopropionyl.

(vii) R ^U CO-, where R ^{u has} the definition given in (i). Examples of such groups include benzoyl, substituted benzoyl (e.g. aminobenzoyl), 4-isoxazolyl- and substituted 4-isoxazolylcarbonyl, cyclopentane carbonyl, sydnoncarbonyl, naphthoyl and substituted naphthoyl (e.g. 2-ethoxynaphthoyl), quinoxalinylcarbonyl and substituted-quinoxalinyl carbonyl (e.g. quinoxalinylcarbonyl). Other possible substituents for benzoyl include alkyl, alkoxy, phenyl, carboxy, alkylamido, cycloalkylamido, allylamido, phenyl- (lower) -alkylamido, morpholinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, tetrahydropyridino, furfurylamido or N-alkyl-N-anilino or the derivatives thereof, and such substituents can be in the 2- or 2- and 6-positions. Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. If the group R ^{u is} a substituted 4-isoxazolyl group, the substituents listed above under (i) can occur. Examples of such 4-isoxazolyl groups are 3-phenyl-5-methyl-isoxazol-4-yl-carbonyl, 3-o-chlorophenyl-5-methyl-isoxazol-4-yl-carbonyl and 3- (2,6-dichlorophenyl) - 5-methyl-isoxazol-4 ~ yl-carbonyl '..

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(viii) R ^U -CH-CO-, wherein R ^{u is} the one given under (i)

Definition and X has amino, substituted amino (for example Acylamido) or a group which can be obtained by reacting the oc-aminoacylamido group of the 7-side chain with an aldehyde or ketone, for example acetone, methyl ethyl ketone or ethyl acetoacetate, is obtained, hydroxy, carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halogen, acyloxy (for example formyloxy or lower alkanoyloxy) or represents an etherified hydroxy group. Examples of such acyl groups are oc-aminophenylacetyl and cc-carboxyphenylacetyl.

R ^X
(ix) R ^y -C-CO-, wherein R ^x , R ^y and R ^{z are the} same or

R ^Z

can be different and each is lower alkyl, phenyl or substituted phenyl or R ^{x is} hydrogen. An example of such a group is triphenylcarbonyl.

(x) R ^U -NH-C-, where R ^{u has} the definition given in (i) and can additionally denote hydrogen, lower-alkyl or halogen, substituted lower-alkyl and Y denotes oxygen or sulfur. An example of such a group is

(xi) (CH) ^^ C-CO-, where X is the same as in (viii)

gegeoene above definition has, and η is an integer of 1 to 4. An example of such an acyl group is 1-aminocyclohexanecarbonyl.

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(xii) aminoacyl, for example

R ^W CH (NH ₂ ). (CH ₂ ) _n CO, where η is an integer from 1 to 10, or NH ₂ .C _n H _2n ArCCH ₂ ) _m CO, where m is O'or an integer from 1 to 10 and η is 0, 1 or 2, R ^{w is} a hydrogen atom or an alkyl, aralkyl or carboxy group or a group as defined above for R ^u , and Ar is an arylene group, for example p-phenylene or 1, 4-naphthylene, means. Examples of such groups are described in British Patent 1,054,806. One group of this type is the p-aminophenylacetyl group. Other acyl groups of this type include those, for example 6 aminoadipoyl, which are derived from naturally occurring amino acids and their derivatives, for example N-benzoyl- <£ - aminoadipoyl.

(xiii) Substituted glyoxylyl groups of the formula R ^y .CO.CO-, where R ^{y is} an aliphatic, araliphatic or aromatic group, for example a thienyl group, a phenyl group or a mono-, di- or trisubstituted phenyl group, the substituents for example being one or several halogen atoms (F, Cl, Br or J), methoxy groups, methyl groups or amino groups or a condensed benzene ring. The cc-carbonyl derivatives of the above substituted glyoxylyl groups, for example the oc-hydroxyimino, oc-alkoxyimino and a-acyloxyimino derivatives, in particular those, dJ ? have syn configuration includes.

(xiv) formyl.

(xv) hydrocarbyloxycarbonyl and substituted hydrocarbyloxy groups (wherein the 7-amino group forms part of a urethane), particularly lower alkoxycarbonyl groups (such as methoxycarbonyl, ethoxycarbonyl and most preferably t-butoxycarbonyl groups), halogen-lower alkoxycarbonyl groups, for example 2,2,2-trichloroethoxycarbonyl, aralkoxycarbony! groups such as benzyloxycarbonyl, 4-methoxy

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benzyloxycarbonyl, diphenylmethoxycarbonyl and 4-nitrobenzyloxycarbonyl groups. Cycloalkoxycarbonyl groups are also advantageous, especially the adamantyloxycarbonyl group.

(xvi) haloformyl, for example chloroformyl.

Specific ester groups -COOR which may be present in the compounds of the formulas II and III include those which are given in the following list, the compounds listed are only examples of possible ester groups.

(i) -COOCR R ^S R, in which at least one of the radicals R, R ^s and R is an electron donor, for example p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxy or fur-2 -yl. The remaining groups R, R ^s and R can denote hydrogen or organic substituent groups. Suitable ester groups of this type include p-methoxybenzyloxycarbonyl and 2,4,6-trxmethylbenzyloxycarbonyl.

(ii) -COOCR R%, wherein at least one of the radicals R, R ^ and R is an electron-attracting group, for example benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyano methyl, ¹ ethoxy carbonylmethyl, aryl sulf ony Im ethyl, 2-dimethylsulfonium methyl, o-nitrophenyl or cyano. The remaining groups R, R ^s and R can represent hydrogen or an organic substituent group. Suitable esters of this type include benzoyl methoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridyl methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl.

(iii) -COOCR ¹ ^ R ⁰ R ¹¹ , vrorin at least two of the radicals R, R ^ and R denote a hydrocarbon group such as alkyl, for example methyl or ethyl, or aryl, for example phenyl, and the remaining groups R ^f , R ^s and R ^h , if present, mean V / ace material. Suitable esters of this type include t-butyloxycarbonyl, 1-amyloxycarbonyl, diphenyl

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methoxycarbonyl and triphenylmethoxycarbonyl.

(iv) -COOR ¹ , where R ^{1 is} adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl or tetrahydropyran-2-yl.

(ν) Silyloxycarbonyl groups obtained by reacting a carboxyl group with a derivative of a silanol. A halosilane or a silazane of the formula is expediently used as a derivative of a silanol

(R ^U ) ₃ SiD; (R ¹³ O ₂ SiD ₂ ; (R ^U ) ₃ Si.N (R ^U ) ₂ ; (R ⁿ (R ^{1: L} ) ₃ ; (R ¹¹ ^ Si.NH.COR ¹¹ ; (R ¹¹ ) ₃ Si .HN.CO.NH.Si

R ¹¹ NHXO-NR ¹¹ ^ i (R ¹³ ") ₃ ;. R ¹¹ C [OSi (R ¹¹ ) ₃ ]: ₃

11 wherein D is a halogen atom and the various groups R, which may be the same or different, are hydrogen atoms or alkyl, for example methyl, ethyl, n-propyl, isopropyl groups, aryl, for example phenyl groups, or Aralkyl, for example benzyl, groups. Preferred Derivatives of silanols are silyl chlorides such as trimethylchlorosilane and dimethyldichlorosilane.

The carboxyl group can be selected from an ester according to any of the following conventional methods are regenerated, for example acid and base catalyzed hydrolysis is generally applicable, one can also use enzymatically catalyzed hydrolysis. However, aqueous mixtures are for these compounds are poor solvents and can cause isomerization and rearrangement, side reactions and general Effect degradation so specific procedures may be desirable.

Five suitable ester cleavage processes are given below listed.

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(1) Reactions with Lewis acids

Suitable levo acids for reaction with the esters include trifluoroacetic acid, formic acid, hydrochloric acid in acetic acid, zinc bromide in benzene and aqueous solutions or suspensions of mercury (II) compounds. The reaction with the lev / io acids can be facilitated by adding a nucleophile such as anisole.

(2) reduction

Suitable systems to effect the reduction are zinc / Acetic acid, zinc / formic acid, zinc / lower alcohol, zinc / pyridine, palladium-on-charcoal and hydrogen and Sodium and liquid ammonia.

(3) attack by nucleophiles

Suitable nucleophiles are those which contain a nucleophilic oxygen or sulfur atom, for example Alcohols, mercaptans and water.

(4) Oxidative processes

for example those in which hydrogen peroxide and acetic acid uses v / earth.

(5) irradiation

The invention also relates to new compounds of the formula

R R

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wherein (R ^a ) an amino, protonated amino or acylamido, group,

(R) a hydrogen atom or a carboxyl protecting group mean,

R ^c , R, Z and the dashed lines have the meanings given above and

R, R · ³ and R, which can be identical or different, each represent hydrogen, lower-alkyl, lower-alkenyl, alicyclic, aryl or aralkyl groups, or where two or more of the groups R, R and R together with the bonded carbon atom can form a cyclic structure and any of the remaining groups R, R- ⁵ or R are a lower-alkyl, lower-alkenyl, alicyclic, aryl or aralkyl group, with the proviso that at least

CD
one of the groups R, R is an organic group when any of the groups R, R ^ and R is a hydrogen atom,

and the carboxylates or acid addition salts thereof, if such can be formed.

Valuable compounds of this class include:

2,2,2-trichloroethyl (6R, 7R) -3- "benzyl-7-frmamidoceph-3-em-4-carboxylate and the 1S oxide of it,

2,2,2-trichloroethyl (6R, 7R) ^ -amino ^ -benzylceph ^ - em-4-carboxylate hydrochloride and the 1S-oxide thereof,

2,2,2-trichloroethyl (6R, 7R) ^ -benzyW-phenoxyacetamidoceph-3-er; 1-4-carboxylate and the 1S oxide of it,

(6R, 7R) -3-Benzyl-7-phenoxyacetamidoceph-3-em-4-carboxylic acid,

2,2,2-trichloroethyl (6R, 7R) -3-benzyl-7- (2'-thienylacetamido ) -ceph-3-era-4-carboxylate and the 1S-oxide thereof,

(6R, 7R) -3 ~ Benzyl-7- (2'-thienylacetamido) -ceph-3-em-4-carboxylic acid,

(2 «R, 6R, 7R) -7- (2'-aminophenylacetaraido) -3-benzylceph-3-e. ^T n-4-carboxylic acid,

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chlpräthoxycarbonylamino] -phenylacetamido) -eeph - ^ - em-A-carboxylate and the 1S oxide of it,

t-Butyl (1S, 6R, 7R) -3- (2 ^l -roethyl-1 *, 3 · -dithiane-2'-ylmethyl) -7-pheliöxyacetamidoceph-3 - em ~ 4 - carboxylate, 1 -oxide ,

t-Butyl (6R, 7R) -7-phenoxyacetamido ~ 3 ~ (2'-phenyl-1 ^f ^ '- dithiolane ^' - ylmethylJ-ceph-J-em ^ -carboxylate and the

1S oxide thereof,

(6R, 7R) -7-Phenoxyacetamido-3- (2 ^s -phenyl ~ 1 ^!, 3'-dithiolane -ylmethylJ-ceph-S-em ^ -carboxylic acid,

Dipheny! Methyl (1S, 6R, 7R) -7-formamido) -3- (2 ^! -Phenyl-1 ^! _I 3 ^l -dithiolane-2 ^! -Ylmethyl) -ceph-3-era ~ 4-carboxylate, 1- Oxide,

t-Butyl (6R, 7R) -3- (1 ^!, 3'-dithiane-2'-ylmethyl) -7-phenoxyacetamidoceph-3-em-4-carboxylate and the 1S-oxide thereof,

(6R, 7R) -3- (1 '»3 ^! -Dithiane-2» -ylmethyl) -7 -phenoxyacetamidoceph-3-em-4-carboxylic acid,

Diphenylmethyl (1S, 6R, 7R) -3- (1 ^!, 3'-dithiane-2 * -ylmethyl) -7-formamidoceph-3-em-4-carboxylate-1-oxide and

2,2,2-trichloroethyl (1S, 1 ¹ R and S, 6R, 7R) -7-formamido-3- (1'-phenylethyl) -ceph-3-em-4-carboxylate-1-oxide.

Compounds of the formula III in which R = H and which have a Λ configuration have antibiotic activity and are thus of value in human and veterinary medicine.

Unless otherwise specified, the following procedures and conditions were used.

The melting points were determined on a Kofler block and are not corrected. The optical rotations were in Dimethyl sulfoxide solution determined between +20 and + 27 ° at concentrations of li 0.3 ^. The ultraviolet spectra were determined in ethanol solutions. The infrared spectra were measured using nujol films. The NMR Spectra were at 60 or 100 MHz in hexadeuteriodimethyl sulfoxide certainly. In each case the spectra agreed

■ 309885 / U42

of the assigned structure. The organic solutions were dried by storing them over anhydrous magnesium sulfate. The solids were dried in vacuo at room temperature (about 1 mm / 25 °), the analytical samples were dried at +40 ⁰ C in vacuo. The following solvents were dried by passing them through a column of basic aluminum oxide (Woelm, activity 1): tetrahydrofuran, Ν, Ν-dimethylformamide, hexamethylphosphoric triamide, 1.2 _r dichloroethane, ether. The solvent 1,2-dimethoxyethane was dried in this way, then allowed to stand over sodium hydride or lithium aluminum hydride and then distilled off from the hydride. The gases, oxygen and nitrogen, were dried by passing them through concentrated sulfuric acid and then over potassium hydroxide. The peracetic acid was an approx. 40% solution in acetic acid. The main impurities such as formic or mineral acid were removed from the ethyl formate by washing with a solution of sodium bicarbonate. All temperatures are in ⁰ C.

Example 1

2,2,2-trichloroethyl (1S, 6R ₁ 7R) -3-ethyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide

a) A solution of 1.15 M methyl-lithium in ether (21.7 ml, 25 mmol) became a suspension of copper (I) bromide (1.82 g, 12.7 mmol) in ether (10 ml) at -10 to 0 ° in a dry nitrogen atmosphere. The solution then became cooled to -70 ° and a solution of 2,2,2-trichloroethyl (iS, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate-1-oxide (2.303 g, 4.9 mmol) in tetrahydrofuran (60 ml) was added under Stirring at -60 to -70 ° added. Additional tetrahydrofuran (20 ml) was added at -60 to -70 ° and the mixture was cooled then stirred at -70 to -75 ° for 11/2 hours. Saturated Aqueous ammonium chloride (20 ml) was added at -55 to -70 ° and the mixture was partitioned between methylene chloride

.-309885/1442

(200 ml) and water (100 ml) distributed. The aqueous layer was washed with methylene chloride (100 ml) and the combined organic layers were dried and filtered through kieselguhr and evaporated to give a pale yellow gel which was triturated with methanol (ca 5 ml) to give the title compound as colorless , crystalline solid (1.011 g, 2.5 mmol, 51%, m.p. 172-174 °, [cc] _D + 88.6 °, X _max 269 nm (£ 7750).

In a manner similar to that described in Example 1 (a) with with the exception that tetrahydrofuran was used as the solvent in the formation of the lithium dimethyl cuprate, the tests listed in Table I were carried out.

309885 / 1U2

Table I.

Further conversions of 2 ', 2', 2 ^! ~ Trichloroethyl (1S, 6R, 7R) -3-bromoethyl-7-formamidoceph-3-em-4-. carboxylate, 1-oxide with lithium dimethyl cuprate

Ex. From / ^ ar. ^ Smnterial vol.

Cg) (rrJ'ioi; TKF for SMCmI)

Cu X

CS /

Vol.THF for CuXCmI)

product

^ Yield

L «j

15.947
_to 1 (c) 18.743
5

S Ke) 10

34 1000 40 600 10.7 120

21.4

Cu Br 12.609 "

Cu J 9.562 50.2

Cu J 3.05 15.8

Cu J +++ 5.70 '

(nBu) -P 6.09

7.741 56.5

9,952 61.6

+0.84 45.6

++ 1.137 46.1

3.901 45

+ 75.6 ° 268 nm 7230 +93.1 268.5 6550 +81.6 269 7230 +61.0 270 6830 +89.0 269 7470

J ^ Notes for the table:

+ 43% of the reaction solution was worked up in the usual way 57% of the reaction solution was worked up by passing dry oxygen through the Reaction mixture at -75 ° for 1/2 hour passed and gut with aqueous ammonium chloride hydrolyzed

The Cu J was dissolved in a solution of (nBu) JP in THF. It was assumed that the following Complex species were formed [Cu J {(nBu), P? ] ,.

Ca> CO

Example 2

Diphenylraethyl (1S, 6R, 7R) -3-ethyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide

i) Diphenylmethyl (6R, 7R) ^ -
carboxylate, hydronitrate salt (44.4 g, 100 mmol), sodium bicarbonate (22 g), water (500 ml) and methylene chloride (500 ml) were stirred together until all solids had dissolved. The aqueous layer was washed with methylene chloride (2 × 200 ml) and the combined organic layers were washed with water (400 ml), dried and evaporated. The residue was dissolved in ethyl formate (11) and formic acid (1 ml) was added and the solution was then refluxed for 5 hours, left to stand at +20 to + 25 ° for 3 days and then evaporated. The residue was dissolved in methylene chloride (2 1/2 l) and cooled to + 5 ° and stirred while peracetic acid (1.1 equiv.) Was added at +5 to + 6 °. The solution was washed with water (11), then with 3% aqueous sodium bicarbonate solution (11) and then dried and evaporated. The remaining solid was dissolved in 1,2-dichloroethane (2.5 l) and reacted for 2 hours at -10 ° with 1,3-dibromo-5,5-dimethylhydantoin (21.46 g, 75 mmol), with ultraviolet light was initiated throughout the reaction (a 125 W medium pressure and a 150 Vi high pressure arc were used, both with Pyrex filters). The solution was washed with 1% sodium bisulfite solution (11) and with water (600 ml), then dried and evaporated. The residue was triturated with tetrahydrofuran (100 ml) and evaporated to dryness. More tetrahydrofuran (200 ml) was added and the suspension was cooled at + 5 ° for 8 hours. Diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide was isolated as a colorless, crystalline solid (29.396 g, 58.3 mmol, 5896), [α ] -19.7 °, λ _maY 278.5 nm (t8860). The NMR spectrum of this product was very similar to that of an authentic sample.

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ii) (a) 1.33 molar methyl lithium in ether (6 ml, 7.96 mmol) was distilled over to a suspension of copper (I) broraide (574 mg »4.0 mmol) in tetrahydrofuran (30 ml Lithium aluminum hydride) given at -20 ° in a dry nitrogen atmosphere. The solution was cooled to -75 ° and stirred while a solution of diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide (1.06.g, 2.10 mmol, containing about 3% of the corresponding 3-methyl compound) in 1,2-dimethoxyethane (90 ml) was added in the course of 3/4 hours at -70 to -75 °. The yellow-orange suspension was stirred at -75 ° for 11/2 hours and then worked up by adding saturated aqueous ammonium chloride solution (5 ml) at -50 to -75 °. The mixture was partitioned between methylene chloride (250 ml) and water (200 ml) and the aqueous layer was washed with methylene chloride (2 × 70 ml). The combined organic layers were washed with water-saturated aqueous ammonium chloride solution (1: 1) (5 x 100 ml), then dried and evaporated to give a pale yellow solid. Trituration with ether gave the title compound as a pale yellow powder (696 mg, 1.588 mmol, 75.4%), [cc] _D + 34.4 °, λ _max 265 nm ( B 7860). Recrystallization from hot methanol gave the analytical sample, melting point 214 to 215 ° (dec.), [A] _n + 49 °, * _mQV 264.5 nm (£ 8850).

ii) (b) Copper (l) iodide (56Ο mg, 2.94 mmol) was partially dissolved in a solution of tri-n-butylphosphine (0.73 ml, 2.92 mmol) in 1,2-dimethoxyethane (50 ml) dissolved. A solution of 1.45 molar methyl lithium in ether (4.05 ml, 5.86 mmol) is added to this suspension at -20 ° in a dry nitrogen atmosphere. The mixture is then cooled to -75 ° and stirred while a solution of diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide (1.004 g, 1.995 mmol , which contains about 3% of the corresponding 3-methyl compound) in 1,2-dimethoxyethane (68 ml) is added in the course of 1/2 hour at -70 to -75 °. The mixture is stirred at -75 ° for up to 30 minutes and then saturated by adding

'309885 / 14U

Aqueous ammonium chloride _v (10 ml) worked up at -65 to -75 °. The reaction mixture is partitioned between methylene chloride (100 ml) and water (100 ml). The aqueous layer is washed with methylene chloride (2 × 50 ml) and the combined organic layers are successively aqueous ammonium chloride solution saturated with 1: 1 with v / water (50 ml) and water. (50 ml), then dried and evaporated to give a pale yellow solid. Trituration with ethyl acetate gives an off-white solid which is dissolved in refluxing methanol (30 ml). and then the solution is allowed to cool slowly. The title compound is obtained as colorless crystals (419 mg, 0.956 mmol, 48%), [a] _D + 42 °, A _max 265 nm (£ -9500).

ii) (c) A reaction similar to that described in Example 2 (ii) (a), with the exception that the lithium dimethyl cuprate is formed in 1,2-dimethoxyethane, is carried out using the following amounts: Copper (I) bromide (2.87 g, 20 mmol) in 1,2-dimethoxyethane (150 ml), methyl lithium in ether (1.33 molar, 30 ml, 40 mmol), the 3-bromomethy compound used as starting material (5, 30 g, 10.5 mmol, which contains about 3% of the 3-methyl compound) is suspended in 1,2-dimethoxyethane (450 ml). The title compound becomes a pale yellow solid (4.22 g, 9.64 mmol, 91> 6%). ..., ..:

ii) (d) A reaction similar to that described in Example 2 (ii) (c) is carried out, except that the 3-bromomethyl compound used as the starting material (containing about 3% 3-methyl compound) as Solid is added using the following amounts: copper (I) bromide (1f725 g, 12.05 mmol) in 1,2-dimethoxyethyne (160 ml) methyl lithium in ether (1.35 molar, 17.8 ml, 24 mmol), starting? 3 = bromomethy compound (2.95 g, 5.86 rnMoi). The title compound is obtained as a very pale yellow solid (2 _? 2621 g, mMo.l,

3Q988S / U42

f COP "

Example 3,.

t-Butyl (1S, OR, 7R) -S-ethyl ^ -phenoxyacetamidoceph-S-em ^ -carboxylate, 1-oxide

A solution of 1.75 molar methyllithium in ether (10 ml, 17.5 mmol) is converted into a cooled (0 to -5 °) suspension of copper (I) iodide (1.67 g, 8.75 mmol ) in ether (20 ml) and the solution is then cooled to -63 °. A solution of t-butyl (1S, 6R, 7R) -3-bromomethyl-7-phenoxyacetamidoceph-3- is added to this now yellow suspension. em-4-carboxylate, 1-oxide (877.9 mg, 1.75 mmol) in tetrahydrofuran (20 ml) at a temperature between -63 and -75 °. After stirring for 1/2 hour at -75 °, Aqueous ammonium chloride is added and the mixture is partitioned between methylene chloride and water. The organic layer is combined with the methylene chloride washing solution of the aqueous layer, filtered, dried and evaporated. The remaining gel is dissolved in 1,2-dichloroethane and restored _{Evaporated to dryness, the title compound} remaining as an opaque, glass-like mass (711 mg), λ maY 267, 273 (inflection point) nm (£ 7210; 6860). '

! Πα. Α.

Example 4

t-Butyl (6R, 7R) -3-ethyl-7-phenoxyacetamidoceph-3-em-4-carboxylate

A solution of 1.75 molar methyl lithium in ether (10 ml, 17.5 mmol) becomes a suspension of copper (I) iodide (1.67 g, 8.75 mmol) in ether (10 ml) at -10 to 0 ° in drier Nitrogen atmosphere added. The mixture is then on -65 ° cooled and stirred while a solution of t-butyl (6R, 7R) -3-bromomethyl-7-phenoxyacetamidoceph-3-em-4-carboxylate (849 mg, 1.75 mmol) in tetrahydrofuran (20 ml) at -65 to -75. More tetrahydrofuran (10 ml) is added at -65 to -75 are added and the mixture is stirred for 1 hour at -75 and then by adding an aqueous ammonium chloride solution (10 ml) containing concentrated hydrochloric acid (2 ml) hydrolyzed at -50 to -60 °. the Mixture between methylene chloride (70 ml) and water

30 98857 1U2

COPY

(70 ml) and the aqueous layer is washed with methylene chloride. The combined organic layers are dried and evaporated to give a yellow foam which was chromatographed on Kiegelgel G in benzene: ethyl acetate (1: 1) to give a sample of the title compound as a foam (194 mg, 0.463 mmol, 26, 4%), [a] _D + 65.6 °, Λ _max 268, 264 (turning point), 273.5 (turning point) nm (£ 6660, 6330, 5950).

Example 5

Diphenylmethyl (1.S, 6R, 7R) -7-formamido-3-n-pentylceph-3-em-4-carboxylate, 1-oxide

a) A solution of 2.11 molar n-butyllithium in hexane (8.75 ml, 18.5 mmol) is added to a suspension of Kupier (I) iodide (1.771 g, 9.3 mmol) in tetrahydrofuran (20 ml ) added at -50 ° in a dry nitrogen atmosphere. The black suspension is cooled to -75 ° and stirred while a solution of diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7-formamidocpeh-3-em-4-carboxylate, 1-oxide (1.862 g, 3, 7 mmol) in hexamethylphosphoric triamide (4 ml), N, N-dimethylfornamide (10 ml) and tetrahydrofuran (26 ml) is added over the course of 1 hour at -65 to -70 °. After stirring for 1 hour at -75 °, the reaction mixture is worked up by adding saturated aqueous ammonium chloride solution (10 ml) at -40 to -75 ° and then the resulting mixture between methylene chloride (200 ml) and water (200 ml ) distributed. The aqueous layer is washed with methylene chloride (2 × 100 ml) and the combined organic layers are filtered, washed with water (2 × 200 ml) and then dried and evaporated to give a brown oil. Chromatography of this oil on silica gel G in methylene chloride: acetone (1: 1) gives the title compound as a colorless, crystalline solid (426 mg, 0.886 mmol, 24%), melting point 162 ° to 169 ° (decomp.), Da] ₀ +45 , 6 °, 7l _max 265.5 nm (£ 9260).

309885 / U42

b) 2.44 molar n-butyl lithium in hexane (4.1 ml, 10 mmol) is added to a solution of tetrakis - [, iodo- (tri-n-butylphosphine) copper (I)] (1.972 g, 1, 25 mmol) (prepared as described by GBKauffman et al, Inorg.Synth. 19, 1963) in tetrahydrofuran (25 ml) at -60 to -70 ° in a dry nitrogen atmosphere. A solution of diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide (525.7 mg, 1.04 mmol) is added to this pale brown, clear solution in N, N-dimethylformamide (5 ml) and tetrahydrofuran (7 ml) at -69 to -75 ° over 15 minutes, more tetrahydrofuran (7 ml) is added and the reaction mixture is left at -75 ° for 11/4 hours The mixture is partitioned between ethyl acetate (70 ml) and water (50 ml), the aqueous layer is washed with ethyl acetate (30 ml) and the combined organic layers are washed with Brine (3 x 50 ml), then dried and evaporated to give a brown gum. Chromatography of the gum on silica gel G in methylene chloride: acetone (1: 1) gives the title compound as a pale yellow solid (140 mg, 0.291 mmol, 28 %) , TV 265 mn (£ 7,780).

Example 6

(2'R, OR, 7R) -7- (2-aminophenylacetamido) -3-n-pentylc eph-3-em-4-carboxylic acid, Hydrochloride

i) A solution of 2.44 molar n-butyllithium in hexane (4.1 ml, 10 mmol) is added to a solution of tetrakis [iodine (trin-buty! Phosphine) copper (I)] (1.991 g, 1.25 mmol) in tetrahydrofuran (25 ml) at -40 ° in a dry nitrogen atmosphere added. The clear, pale brown solution is cooled to -70 ° and stirred while a solution of t-butyl (1S, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate, 1-Oxide (387.5 mg, 0.985 mmol) in tetrahydrofuran (14 ml) over the course is added from 15 minutes at -67 to -70 °. The weak

309885/1442

The brown mixture is stirred at -75 ° for 30 minutes and then stirred while oxygen is passed through the reaction mixture at -73 ° for 30 minutes. The black mixture is mixed with saturated aqueous ammonium chloride solution (TO ml) at -50 to: -73 ^o hydrolyzed and partitioned between ethyl acetate (70 ml) and water (100 ml) The organic layer is combined with the ethyl acetate washing solution (70 ml) of the aqueous layer and washed with water XZ 50 ml), then dried Chromatography of the residue on silica gel G in methylene chloride: acetone (2: 1) gives t-butyl (1S, 6R, 7R) -7-formamido-3-n-pentylceph-3-em-4-carboxylate, 1 Oxide as a yellow gum (105 mg, .0.284 mmol, 28, i

A small sample of this compound is purified by dissolving it in methyl chloride and adding ether to precipitate the compound. This material has the following constants: A _n , "265 nm (£ 9100).

ii) A solution of t-butyl (1S, 6R, 7R) -7-formamido-3-npentylceph-3-em-4-carboxylate, 1-oxide (379 mg, 1.02 mmol) in methanol (7 ml) and ether (7 ml) is cooled in an ice bath and stirred with phosphorus oxychloride (0.234 ml, 2.55 mmol). Crystallization of the product is induced by rubbing the walls of the reaction flask after 10 minutes. The mixture is then cooled to -15 ° for 11/2 hours and the t-butyl (1S, 6R, 7R) -7-amino-3-n-pentylceph-3-em-4-carboxylate, 1-oxide, hydrochloride is isolated by filtration as a colorless, crystalline solid (226.8 mg, 0.598 mmol, 58.7%), melting point 163 to 168 ° (decomp.), [a] _D [91.4 °, Λ _max 265 nm ( £ 9200). Concentration of the mother liquors gives a second batch of the title compound (42.9 ing, 0.113 mmol, 11%), Λ _mov 265 nra (£ .8940).

iii) t-Butyl (1S, 6R, 7R) -7-amino-3-n-pentylceph-3-em-4-carboxylateji-oxide hydrochloride (810.8 mg, 2.14 mmol) is poured into a dividing funnel with ethyl acetate (50 ml) and 3fcLger aqueous sodium bicarbonate solution (25 ml) shaken. The orga-

309885/1442 ^: "

copy;.

The niche layer is combined with the ethyl acetate washing solution (20 ml) of the aqueous layer and washed with saturated aqueous ammonium chloride solution (10 ml) and then cleared by passage through a phase separation paper. Evaporation of the filtrate gives a colorless, crystalline solid which is dissolved in methylene chloride and dried by passing through basic aluminum oxide (20 ml) and treated with a solution of 2R- (t-butoxycarbonylamino) phenylacetic acid (627.2 mg, 2.5 mmol ) is stirred in dry methylene chloride (10 ml). A solution of !!, N-dicyclohexylcarbodiimide (516.7 mg, 2.5 mmol) is added to this solution and the reaction mixture is then stirred at + 5 ° for 16 hours. The suspension is filtered and the filtrate is evaporated to a pale yellow gel which is dissolved in ethyl acetate and filtered. The filtrate is washed successively with hydrochloric acid (30 ml), 35% aqueous sodium bicarbonate solution (30 ml), saturated aqueous ammonium chloride solution (20 ml) and then filtered through a phase separation paper and evaporated. Chromatography of the remaining solid on silica gel G in benzene: ethyl acetate (2: 1) gives the t-butyl (1S, 2'R, 6R, 7R) -7- [2 ^f - (t-butoxycarbonylamino) -phenylacetamido] -3- n-pentylceph-3-em-4-carboxylate, 1-oxide as a colorless, amorphous solid (1.029 g, 1.788 mmol, 83%), [a] _D + 21.7 ° (CHCl ₃ ), X _max 264.5 nm (£ 8920). ''

iv) A solution of t-butyl (1S, 2 ^! R, 6R, 7R) -7- (2 «- [t-butoxycarbonylamino] -phenylacetamido) ^ -n-pentylceph ^ -em ^ -carboxylate, 1-oxide ( 920 mg, 1.598 mmol) in N, N-dimethylformamide (20 ml) is cooled to + 5 ° and stirred with potassium iodide (830 mg, 5 mmol) and acetyl chloride (0.18 ml, 2.54 mmol). After stirring at + 5 ° for 16 hours, similar amounts of potassium iodide and acetyl chloride are added and stirring is continued for 1 hour at +20 to + 25 °. The mixture is then partitioned between ethyl acetate (100 ml) and dilute aqueous sodium metabisulphite solution (approx. 60 ml). The organic layer is washed with 1: 1 water-saturated aqueous ammonium chloride solution (4 × 70 ml), then with 3% aqueous solution

309885/1442

Γ COPY

Sodium bicarbonate solution (70 ml) and then with dilute ammonium chloride solution (70 ml). The solution is then passed through a phase separation paper (Wahtman No. 1PS) and evaporated to give a foam which is chromatographed on silica gel G in benzene: ethyl acetate (2: 1), the t-butyl (2'R, 6R, 7R) -7- [2 ^I - (t.butoxycarbonylamino) -phenylacetamido] -3-n-pentylceph-3-em-4-carboxylate is obtained as a pale yellow foam (743.5 mg, 1.33 mmol, 83% ), [a] _D + 6.5 ° (CHCl,), A _mQY 264 mn (£ .7840).

v) t-Butyl (2 ¹ R, 6R, 7R) -7- [2 · - (t-butoxycarbonylamino) -phenylacetamido] -3-n-pentylceph-3-em-4-carboxylate (667 mg, 1.192 mmol) is treated with trifluoroacetic acid (10 ml) for about 1 hour and then the solution is evaporated to dryness. The remaining material is dissolved in 2N hydrochloric acid (100 ml), washed with ether (2 × 30 ml) and then combined with the aqueous washing solutions of the ether layers and evaporated on a rotary evaporator at 40 ° for 10 minutes and then freeze-dried. The pale yellow glass that is obtained is dissolved in water (90 ml) and freeze-dried to give the title compound as an almost colorless solid (461 mg, ca 1.05 mmol, 94%), Λ _mQV 262 (£ 6450 ).

Example 7
(6R, 7R) -3-Benzyl-7-phenoxyacetamidoceph-3-em-4-carboxylic acid

i) (a) A solution of 1.725 molar phenyllithium in ether-benzene (58 ml, 100 mmol) is made into a suspension Copper (I) iodide (9.56 g, 50 mmol) in tetrahydrofuran (150 ml) was added at -40 ° under a dry nitrogen atmosphere. The resulting black suspension is cooled to -75 ° and stirred while a solution of 2,2,2-trichloroethyl (1S, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate, 1-Oxide (4.68g, 10mmol) in tetrahydrofuran (200ml) over 11/2 hours is added at -70 to -75 °. The mixture is at -75 °

309 8 85 / U42

stirred for 2 hours and worked up by adding saturated aqueous ammonium chloride solution (50 ml) at -65 to -75 °. After the mixture was partitioned between methylene chloride (300 ml) and water (300 ml), the organic layer is combined with the methylene chloride (100 ml) washing solution of the aqueous layer, filtered, washed with water (2 × 200 ml), dried and evaporated, leaving a brown gum. Rubbing this gum with ethanol gives 2,2,2-trichloroethyl (1S, 6R, 7R) -3-benzyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide as an almost colorless solid (1.509 g, 3.24 mmol, 32.4%), m.p. 188-191 ° (dec.). Chromatography of the mother liquors gives a second batch of the above compound as a colorless, crystalline solid, 0.501 g, 1.08 mmol, 10.8%), m.p. 188 to 194 ° (dec.), [Cc] _D +27.2 °, Λ _max 272.5, 262 (turning point), 267.5 nm (turning point), (£ 9740, 8420, 9400).

i) (b) A reaction with copper (I) bromide instead of iodide is carried out in essentially the same manner as described in Example 7 (i) (a) above with the following amounts: Copper (I) bromide ( 7.17 g, 50 mmol) in tetrahydrofuran (150 ml), phenyllithium (1.725 molar, 58 ml, 100 mmol), starting ester (11.7 g, 25 mmol) in tetrahydrofuran (450 ml). The 2,2,2-trichloroethyl (1S, 6R, 7R) -3-benzyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide is obtained by recrystallization in two batches with the following constants: (7 , 4 g, 15.9 mmol, 63.5%), '"I _ev

TtIaX.

272, 262 (inflection point), 268 nm (inflection point) ( E 9800., 8600, 9500) and (0.747 g, 1.6 mmol, 6.4%), λ. _γ 272, 262 (turning point), 268 (turning point) (£ 9640, 8380, 9260).

ii) 2,2,2-Trichloroethyl (1S, 6R, 7R) -3-benzyl-7-formamidoceph-3-em-4-carboxylate-1-oxide (2.177 g, 4.67 mmol) is dissolved in methanol (15 ml) suspended and cooled to + 5 °. Phosphorus oxychloride (Q, 86 ml, 9.34 mmol) is added, the suspended solid dissolving and after 1 minute the product ζμ begins to crystallize. After 11/4 hours at + 5 °, the mixture is cooled at τΐ4 ° for 1 hour and the 2,2,2-Tr4-chlarethyl (1S _f 6jR, 7H) -7 ^ amino-3-benzylceph-3-em- 4-carboxylate,

1-oxide, hydrochloric! is isolated by filtration as a colorless, crystalline solid (1.937 g, 4.1 mmol, 87.550, melting point 189 Ms 194 ° (decomp.), [α] _β -i6 »6 °» A _max 273.5, 262 (turning point ), 268 nm (inflection point) (£ 9440, 8820, 7670).

iii) 2,2,2-Trichloroethyl (1S ₁ 6R, 7R) - ^ - amino ^ -benzylceph-3-em-4-carboxylate, 1-0xyd, hydrochloride (511 mg, 1.075 mmol) is in N, N- Dissolved dimethylfarmamide (7.5 ml) and cooled to 0 to + 10 °. Calcium carbonate (236 mg) and phenoxyacetyl chloride (0.15 ml, 1.075 mmol) are added and the solution is stirred for 1 1/2 hours at 0 to +10. The calcium carbonate is removed by filtration and washed with methylene chloride. The filtrate and the washing solutions are diluted to 150 ml with more methylene chloride and washed with water (2 × 100 ml), combined with the methylene chloride (50 ml) washing solutions of the aqueous layer, then with 2N hydrochloric acid (100 ml), 35oiger aqueous sodium bicarbonate solution (100 ml) and then washed with water / water (100 ml). The organic solution is dried and evaporated to a small volume, whereupon the product begins to crystallize. The suspension is diluted with ether and then filtered, the 2,2,2-trichloroethyl (1S, 6R, 7R) -3-enzyl-7-phenoxyacetamidoceph-3-em-4-carboxylate, 1-oxide as Almost colorless, crystalline solid is obtained (560 mg, 0.98 mmol, 91.250, melting point 192 to 196 ° (decomp.), [a] _D -24.2 °, Λ. _{m & x} (MeOH) 267.5, 274, 262 '(inflection point) nm (£ 10 500, 10 500, 9300).

iv) (a) A cooled (+ 5 °) solution of 2,2,2-trichloroethyl- (1S, 6R, 7R) -3-benzyl-7-phenoxyacetamidoceph-3-em-4-carboxylate, 1-oxide (256 mg, 0.446 mmol) in N, N-dimethylformamide (3 ml) is mixed with potassium iodide (592 mg, 3.56 mmol) and acetyl chloride (0.128 ml, 1.78 mmol) for 11/2 hours. A solution of sodium metabisulfite in water-M, ll-dimethylformamide (1: 1) is added and the yellow suspension is between methylene chloride (50 ml) and water (25 ml) distributed-. The methylene chloride layer is washed with the ether (25 ml) aqueous layer combined and dried and evaporated. That

3Q9885 / U42

Any remaining oil is dissolved in ether (50 ml), washed with water (2 × 25 ml), dried and evaporated. The residue is triturated with ether, the 2,2,2-tri * chloroethyl (6R, 7R) -3-benzyl-7-phenoxyacetamidoceph-3-em-4-carboxylate being obtained as a colorless, crystalline solid (0.113 g, ^υ , 203 mmol, 45.5? °) ', m.p. 107 to 110 °, [α] _β -20.8 °, λ 267, 273.5, 262 (inflection point) nm (£ 9450, 9000, 8950).

Ul el λ

iv) (b) In a manner similar to (iv) (a) above, a sample of 2,2,2-trichloroethyl (6R, 7R) -3-benzyl-7-formamidoceph-3_em-4-carboxylate was prepared from the corresponding 1S-0xyd received. The compound had the following constants: Mp. 116 to 120 °, [cc] _D -41.6 °, * _max 265.5, 271, 261 (inflection point) nm (£ 8400, 835.0, 8070).

This compound (500 mg, 1.11 mmol) was suspended in methanol (15 ml) and treated with a solution of hydrogen chloride (550 mg, 15.4 mmol) in methanol (8 ml) for 1/2 hour at +20 to + Stirred at 25 °. The yellow solution was then evaporated and the remaining QeI (476 mg) was suspended in methylene chloride and cooled to + 5 °. Propylene oxide (0.16 ml, 2.33 mmol) and phenoxyacetyl chloride (0.16 ml, 1.145 mmol) were added and the mixture was stirred for 2 hours. The solution was washed successively with 2N hydrochloric acid (10 ml) and 3% aqueous sodium bicarbonate solution (3 χ 10 ml), then dried and evaporated, the 2,2,2-trichloroethyl (6R, 7R) -3-benzyl- 7-phenoxyacetamidoceph-3-em-4-carboxylate was obtained as a pale yellow foam (300 mg, 0.54 mmol, 48.6? O) »^ max ²⁶⁸ ' ²⁷⁴ > ⁵ » ¹⁶³ (inflection point) nm (£ 8500, 8120, 8060). The NMR spectrum of this foam was similar to that of the product obtained in (iv) (a) above.

v) A cooled (+ 5 °) solution of 2,2,2-trichloroethyl- (6R, 7R) -3-benzyl-7-phenoxyacetamidoceph-3-em-4-carboxylate (502 mg, 0.902 mmol) in 5 # aqueous formic acid (5 ml) was stirred with zinc dust (3.0 g) for 10 minutes and then filtered. The zinc was washed with ethyl acetate and

309885 / UA2

the filtrate and washings were evaporated. The residue was dissolved in ethyl acetate (25 ml) and stirred with water (60 ml) and then the pH was adjusted to 8.0 with 2N sodium hydroxide solution. The organic layer was extracted with 3% sodium bicarbonate solution (2 × 50 ml) and the pH of both aqueous layers was adjusted to pH 2.5 with 2N hydrochloric acid under ethyl acetate. The organic layer was combined with the ethyl acetate washes of the aqueous layer, dried and evaporated to a foam. Trituration of the foam with ether-acetone gave the title compound as a colorless, crystalline solid (213 g, 0.50 mmol, 56%), mp 118.5-126 ° [a] _D + 1.0 °, X _max 263 , 5, 272 (inflection point) nm (£ 10 520, 8700).

Example 8

(6R, 7R) -3-Benzyl-7- (2 «-thienylac et amido) -ceph ^ -em ^ -carboxylic acid

i) An "acylation similar to that described in Example 7 (ii) was carried out, but using 2-thienylacetyl chloride instead of phenoxyacetyl chloride and using the following amounts: 2,2,2-trichloroethyl (1S, 6R, 7R) ^ -amino ^ -benzylceph ^ -em ^ -carboxylate, "Ί-oxide (2.5 g, 5.27 mol) in N, N-dimethylformamide (15 ml), calcium carbonate (1.16 g), 2 -Thienylacetyl chloride (851 mg, 5.33 mmol). The 2,2,2-trichloroethyl (1S, 6R, 7R) -3-benzyl-7- (2'-thienylacetamido) -ceph-3-em-4-carboxylate, 1-oxide was obtained as a crystalline solid (1.705 g , 3.04 mmol, 57.5%), m.p. 188-192 ° (dec.), [A] _D + 44.1 °, A ^ _x 232.5, 272.5, 261 (inflection point), 267 nm (inflection point) (£ 12,900, 9820, 8360, 9430).

ii) A reduction similar to that in Example 7 (iv) is described, but using 2,2,2-trichloroethyl (1S, 6R, 7R) -3-benzyl-7- (2'-thienylacetamido) -ceph-3-em- ■ 4-carboxylate, 1-0xyd (1.684 g, 3.0 mmol) gave a sample of 2,2,2-trichloroethyl (6R, 7R) -3-benzyl-7- (2 «-thienylacetarnido) -

309885 / 1U2

_a i _s lightly tanned crystalline solid (1.30 g, 2.4 mol, 80 Si), melting point 142 to 144 °, [a] _Q -25.2 °, λ _aax 234.5, 259, 265.5, 271 nra (£ 13 OQO, 7850, 8170, 8020).

iii) The treatment of 2,2,2-trichloroethyl (6R, 7R) -3-benzyl'7 '- (2 ¹ »thienylacetamido) -ceph-3-em-4-carboxylate (499 mg, 0.915 mol) with zinc in aqueous formic acid at 5 ° in a manner similar to that described in Example 7 (v) gave a sample of the title compound as a colorless, crystalline solid; (127 mg, 0.207 mol, 32.6%), m.p. 151 to 156 °, [a] _n -1 °, Λ _mQV

LJ . IucL.lv

236, 262 (Y / end point), 267 (turning point) mn (£ 15 090, 10 350, 9700).

B e i s ρ i Q j). G

(2 ¹ R, 6R, 7R) ~ 7 ~ (2'-aminophenylacetamido) -S-carboxylic acid

i) Acylation was carried out in a manner similar to that described in Example 7 (iii), but the (2R) -2- (2 », 2", 2 ¹¹ TrichloräthexyearbqnylaminoJ -phenylacetylchlorid was used as the acid chloride and the following amounts were used: the 7-aroino hydrochloride (2.5 g, 5.27 mmol) in N / N-Dimrfchylforraamid (15 ml), calcium carbonate (1.16 g), acid chloride (5.27 mmol in 3 to 4 ml methyl isobutyl ketone), the 2, 2,2-Triohloroethyl (1S, 2 ^l R, 6R, 7R) ~ 3-benzyl-7 "- [2« - (2 », 2 ^ll , 2" -triehlQratshQxyG & rbpnylamino) -phenylacetamido] -ceph-3-em- 4-carboxylate, 1-oxide was obtained as a crystalline solid (1.845 g, 2.48 mol, 475i), melting point> 220 ° (decomp.), [A] _Q -4.8 °, A _roax 272.5 , 260 (inflection point), 267 (inflection point) nm (£ 9760, 8130, 9320), a single batch of the compound was obtained by digesting the mother liquors and triturating with ether-ethyl acetate (62Θ mg, 0.043.IBMOL ₁ 16Ji), λ _max 272.5, 261 (V / end point), 265 (inflection point) nm (£ 10 390, 8800, 9700).

ii) The IS-oxide produced according to B§i§pita 9 (i) (2.314 g, 3.1 "Wol) vmrdf in a _f a, 2-triehloroethyl (2'R, 6R, 7R) -3-benzyl- "- (2", 2 ", 2" -triehl0ratsho5cycarbonylaminp) '- phenylaoetamidp] - ■

309885/1442

ORIGINAL INSPECTED

^'38' 23370A7

ceph ^ 3 ^ em-'4-carboxylate by a procedure similar to that described in Example 8 (ii). The product had the following constants; (1.732 g, 2.37 mmol, 76 _f 5 ° / E, m.p. 164 to 171 °, OJ _D - ^ 2.7 ⁰ , ^ _max 264.5, 260 (turning point), 270 (turning point) mn (£ 8540, 8180, 8320).

iii) A solution of 2,2,2-trichloroethyl (2 «R, 6R, 7R) -3-benzyl-7« - [2 '- (2 ", 2", 2, "- trichlorathoxycarbonylamino) -phenyl ~ acetamido] «" ceph-3-em ~ 4-carboxylate (503 mg, 0.685 mmol) in aqueous formic acid (30 ml) and ethyl acetate (10 ml) was cooled to 0 to + 10 ° and treated with zinc dust (6 g) stirred for 25 minutes. The zinc was removed by filtration and washed with formic acid. The filtrate and the washing solutions were evaporated to a small volume and passed through a column of Deacidite FF, in formate form, eluting with formic acid and collecting 10 ml fractions. The fractions that had negative rotations were combined and evaporated and the residue was dissolved in water and freeze-dried. The title compound was obtained as a weak yellow solid (330 mg, containing approx. 2Q ° 4 water, approx. 0.623 ml-iol, 91%), [cc] _D -2.5 °, ^ _max 263, 258 (inflection point) nm ( £ 10,000,9760).

Example 1 10 '

(6R, 7R) -3- (1 ^t , 3'-dithiane-2 «-ylmethyl) ^ - phenoxyacetamide-

i) line solution of 1,3-dithiane (3.35 g, 27.2 mmol) in dry tetrahydrofuran (125 ml) was at «* 20 ° with a Solution of ϊΐ-butyllithium in hexane (10 ml, 2 m, 20 mmol) be-Ji - ndflt and stirred under dry nitrogen at «20 to -10 ° for 1.5 hours. The reaction mishap was on -70 ° and a solution of t-

1-oxide

(10.2 g, 20.5 mmol) in dry tetrahydrofuran (200 ml)

added over 1 hour. the

309885 / U42 _ftRlr . _MJII

ORiG ₁ ¹ NAL INSPECTED

The mixture was stirred under dry nitrogen at -70 for 2 hours and a solution of ammonium chloride (5 g) in V / water (50 ml) was added. The mixture was allowed to warm to 19 ° and was poured into ethyl acetate (1 L) and water (1 L). The organic layer was washed with water (50 ml) and dried and the solvent was evaporated to give an orange foam. Chromatography on silica gel G (300 g) eluting with methylene chloride-acetone (8: 1) gave t-butyl (1S, 6R, 7R) -3- (1 · _> 3'-dithiane-2 ^l -ylmethyl) -7 -phenoxyacetamidoceph-3-em-4-carboxylate, 1-oxide as a yellow foam (4.02 g, 34%), [α] _β -14.9 °, A. 268 nm (£ 10,400), 273.5 nm (£ 9750) and inflection point 264 nm (£ 9400).

ii) A solution of t-butyl (1S, 6R, 7R) -3- (i ', 3'-dithian-2'-ylmethyl) -7-phenoxyacetamidoceph-3-em-4-carboxylate, 1-oxide (2 , 8 g, 5.2 mmol) in N, N-dimethylformamide (40 ml) was cooled to -6 ° and potassium iodide (3.5 g, 21 mmol) was added, then acetyl chloride (0.75 ml, 10, 6 mmol) was added. The cooling bath was removed after 5 minutes and the mixture was stirred for a further hour, during which time the temperature rose to 19 °. A solution of sodium metabisulfite (3.16 g, 15.7 mmol) in water (50 ml) was added and the mixture was poured into water (400 ml) and extracted with methylene chloride (3 x 250 ml). The combined extracts were washed successively with water / water (6 250 ml) and saturated aqueous sodium chloride solution (6 100 ml), dried and evaporated to a yellow foam. Chromatography on silica gel G (00 g) eluting with methylene chloride-acetone (10: 1) gave the t-butyl (6R, 7R) -3- (i ', 3'-dithiane-2 ^! -Ylmethyl) -7-phenoxyacetamidoceph -3-em-4-carboxylate as a white foam (1.02 g, 3850, [cc] _D + 39.5 °, ⁷ ^ _8x 268 nm (£ 8600).

iii) t-Butyl (6R, 7R) -3- (1 ', 3'-dIthian-2'-ylmethyl) -7-phen-

oxyacetamidoceph-3-em-4-carboxylate (0.8 x g, 1.53 mmol) was added to Trifluoroacetic acid (8 ml) and anisole (2 ml) dissolved at 20 ° and left to stand for 30 minutes. The excess reagents

309885 / 1U2

were removed in vacuo and the residue was partitioned between 3% aqueous sodium hydrogen carbonate solution (20 ml) and ethyl acetate (2 ml). The organic layer was re-extracted with 3% aqueous sodium hydrogen carbonate solution (10 ml) and the combined aqueous solution. Layers were acidified to pH 2 with hydrochloric acid (2N). The mixture was extracted with ethyl acetate (3 × 50 ml) and the combined extracts were washed with water (2 × 100 ml), dried and evaporated to give the title carboxylic acid as a cream-colored foam (0.67 g, 93%) , [ ⁰ On + 53 °, Λ _max (pH 6 phosphate buffer) .266 nm (£ 10 500), inflection points at 262 nm (£ 10 200) and 272 nm (E 9400).

Example 11

Diphenylmethyl (iS, 6R, 7R) -3- (1 ', 3'-dithiane-2 ^l -yl-methyl) -7-formamidoceph ~ 3-em-4-carboxylate, 1-oxide

A solution of 1,3-dithiane (4.2 g, 35 mmol) in dry tetrahydrofuran (150 ml) was treated at -20 ° with a solution of n-butyllithium in hexane (15 ml, 2 M, 30 mmol) and υ lter dry nitrogen at -20 ° for 1.5 hours. The reaction mixture was cooled to -70 ° and a solution of diphenylmethyl (iS, 6R, 7R) -3-bromomethyl-7-formamidoceph-3-em-4-carboxylate, 1-oxide (5.0 g, 10 mmol) in N, N-Dimethylformamide (30 ml) and tetrahydrofuran (50 ml) were added in bulk over 1 hour. The mixture was stirred under dry nitrogen at -70 ° for 2 hours and saturated aqueous ammonium chloride solution (20 ml) was added. The mixture was allowed to warm to 19 ° and it was then poured into ethyl acetate (500 ml) and water (500 ml). The layers were separated and the organic layer was washed with water. A colorless solid gradually separated out from the solution, this was filtered off, washed with water and ethyl acetate and dried in vacuo, the title ester being obtained as colorless microcrystals (3.9 g, 72%), [a] _D -2 ° .

309885 / U42

Example 12

^ 1-Butyl (1S, 6R, 7R) -3- (2 ^l -methyl-1 ^l , 3 ^t -dithiane-2 ^l -ylmethyl) -7-phenoxyacetamidoceph-3-em-4-carboxylate, 1-oxide

A solution of 2-methyl-1,3-dithiane (4.7 g, 35 mmol) in dry tetrahydrofuran (100 ml) was cooled to -20 ° and treated with a solution of n-butyllithium in hexane (15 ml, 2 m, 30 mmol) and stirred under dry nitrogen for 1.5 hours at -20 °. The solution was cooled to -70 ° and a solution of t-butyl (1S, 6R, 7R) -3-bromomethyl-7-phenoxyacetamidoceph-3-em-4-carboxylate, 1-Oxide (5.0 g, 10 mmol) in dry tetrahydrofuran (100 ml) was added dropwise added over 30 minutes. The reaction mixture was under dry nitrogen at -70 ° during Stirred for a further 2.5 hours, then a saturated aqueous solution of ammonium chloride (10 ml) was added. The mixture was allowed to warm to 21 ° and it was then poured into ethyl acetate (11) and water (1 L). The organic Layer was washed with water (2 × 600 ml) and dried and the solvent was removed in vacuo to give a yellow gel. Chromatography on Kiegelgel G (250 g) and elution with methylene chloride-acetone (4: 1) gave the title ester (2.24 g, 4350, - [corner + 37 °, Λ "269 rim (£ .10,200).

LJ ΙΙΙα, Λ.

Example 13

(6R, 7R) -7 ~ phenoxyacetamido) -3- (2 ^l -phenyl-1 ·, 3'-dithiolane ¹ -ylmethyl) -ceph-3-em-4-carboxylic acid

i) A solution of 2-phaiyl-1,3-dithiolane (994 mg, 5.45 mmol) in dry tetrahydrofuran (25 ml) was heated to -20 ° cooled and treated with a solution of n-butyllithium in hexane (2 ml, 2 m, 4 mmol) and the resulting deep red solution was stirred at -20 to -10 ° under dry nitrogen for 2 hours. The solution was cooled to -75 ° and a Solution of t-butyl (1S, 6R, 7R) -3-bromomethyl-7-phenoxyacetamido * - ceph-3-em-4-carboxyiate, 1-oxide (2.04 g, 4.1 mmol) in dry Tetrahydrofuran (40 ml) was added over 1 hour. the

Reaction was carried out under nitrogen at -70 ° Eiteren during a v / hour, then a solution of ammonium chloride was added (3 _f 0 g) in water (20 ml). The mixture was allowed to warm to 19 °, it was then poured into water (200 ml) and ethyl acetate (200 ml). The organic layer was washed with water / water (2 × 200 ml) and dried and the solvent was evaporated to give a pink foam (2.59 g). Chromatography on silica gel G, eluting with methylene chloride-acetone (4: 1), gave the t-butyl- (1S, 6R, 7R) ^ -phenoxyacetamide ^ - (2 ^! -Phenyl-1 ·, 3 ^! -Dithiolane-2'- ylmethyl) -ceph-3-em-4-carboxylate, 1 ~ 0xyd (611 mg, 25%), [ ^a J _D + 24 ° (c 1.06, DMSO),? * · _v 268 (£ 14,000) , 274 (B13 800), inflection point at 263 nm (£ 12 800).

ii) A solution of t-butyl (iS, 6R, 7R) -7-phenoxyacetamido-3- (2'-phenyl-1, 3'-dithiolan-2'-ylmethyl) -ceph-3-em-4- carboxylate-1-oxide (363 mg, 0.60 mmol) in N, N-dimethylformamide (6 ml) was cooled to 0 ° and treated with potassium iodide (606 mg) and acetyl chloride (142 mg, 0.13 ml). The deep red reaction mixture was stirred at 0 ° for 10 minutes, the ice bath was removed and the solution was stirred for a further 10 minutes. A solution of sodium metabisulfite (200 mg) in water (20 ml) was added and the resulting yellow suspension was poured into water (150 ml). This suspension was extracted with methylene chloride (3 x 50 ml). The combined extracts were washed with water and saturated sodium chloride solution, dried and the solvent was evaporated, whereby the t-butyl (6R, 7R) -7-phenoxyacetamido ~ 3- (2 '-phenyl-1', 3 '-dithiolan 2 '-ylmethyl) -ceph ^ -em ^ -carboxylate was obtained as a pale yellow foam (374 mg), [cc] _D + 51.6 °,'

X 274 (812 200) and 268 ( 1 12 500), turning point at max

263 nm (812,200).

iii) t-Butyl (6R, 7R) -7-phenoxyacetaraido) -3- (2'-phenyl-1 ', 3 ¹ -

Dithiolan-2 ( ¹ -ylmethyl) -ceph-3-em-4-carboxylate (289 mg, 0.47 mmol) was dissolved in trifluoroacetic acid (4 ml) and anisole (1 nil) and the solution was allowed to stand for 20 minutes.

309885 / U42

The reagents were evaporated in vacuo and the gummy residue was partitioned between ethyl acetate (30 ml) and aqueous sodium bicarbonate solution (3% _t 30ml). The organic layer was further extracted with bicarbonate solution (2 × 30 ml). The pH of the combined aqueous solutions was adjusted to pH 2.5 (2N) with hydrochloric acid and then this was extracted with ethyl acetate (3 × -50 ml). The combined extracts were washed with water, dried and the solvent removed in vacuo to give the title carboxylic acid (241 mg, 96%) which was homogeneous as shown by paper chromatography (R _f 0.41, EtOAC : t-BuOH: ph 5 buffer 8: 1: 8, 37 °), [α] _β + 62 °, ^ max ^{268 in} ^ ¹⁰ ^ ⁰⁰ ) ^{and turn} P ^{unkite at 2} » ⁶² (p. 10 100) and 275 nm (£ 900).

Example 14

Diphenylmethyl (1S, 6R, 7R) -7-formamido-3- (2'-phenyl-1 *, 3'-dithiolan-2'-ylmethyl) -ceph-3-em-4-carboxylate, 1-oxide

A solution of 2-phenyl-1,3-dithiolane (6.85 g, 35 mmol) in Tetrahydrofuran (100 ml) was treated at -20 ° with a solution of n-butyllithium in hexane (12.5 ml, 2.4 M, 30 mmol) and stirred under dry nitrogen at -20 ° for 1 hour. The reaction mixture was cooled to -70 ° and a Solution of diphenylmethyl (1 S, 6R, 7R) ^ -bronimethyl ^ -formamidoceph-3-em-4-carboxylate, 1-oxide (5 g, 10 mmol) in N, N-dimethylformamide (30 ml) and tetrahydrofuran (30 ml) was added dropwise added over the course of an hour. The mixture was stirred under nitrogen at -70 ° for 4 hours. Saturated aqueous ammonium chloride solution (20 ml) was added. The mixture was allowed to warm to 20 ° and it would poured into ethyl acetate (500 ml) and water (500 ml). The organic layer was washed with water (3 x 500 ml) and dried and the solvent was removed to give a brown foam. Chromatography on silica gel G (150 g) eluting with methylene chloride: acetone (4: 1) the title ester as a pale yellow foam (1.02 g, 1726), [cc] -8 °.

309885 / U42

Example 15 em-4-carboxylate, 1-oxide

1.5 molar n-butyllithium in hexane (33 × ml, 49.5 mmol) was added to a cold (-60 °) suspension of Küpfer (I) bromide (3.68 g, 25.6 ml'lol) in Tetrahydrofuran '(30 ml) was added, the resulting black mixture was cooled to -75 °. A solution of t-butyl (1S, 6R, 7R) -3-bromomethyl-7- (2'-thienylacetamido) -cephO-em - ^ - carboxylate, 1-oxide (2.5 g , 5.12 mmol) in tetrahydrofuran (70 ml) at -70 to -72 ⁰ C during 45 minutes. The solution was stirred at -75 ° for a further 2 hours and then hydrolyzed at -75 to -50 ° by adding a saturated aqueous ammonium chloride solution (40 ml). The mixture was partitioned between methylene chloride (250 ml) and water (300 ml). The aqueous layer was washed with methylene chloride (100 ml) and the combined organic layers were washed with water (2 × 100 ml), dried and evaporated. The black rubber that remained was chromatographed on Kiegelgel G (100 g) in methylene chloride: acetone (9: 1) and then on three 20 × 20 cm preparative thin-layer plates. The title compound was isolated as a yellow, amorphous solid (109 mg, 0.235 mmol, 4.6 μl).

Example 16

2,2,2-trichloroethyl (1S, 1 «S [or R], 6R, 7R) -7-formamido-3- (1'-phenylethyl) -ceph-3-em-4-carboxylate, 1-0xyd

A solution of 2.08 molar phenyllithium in ether-benzene (1.2 ml, 2.5 mmol) was added to a stirred suspension of copper (I) bromide (0.149 g, 1.04 mmol) in tetrahydrofuran (10 ml) given at -15 ° in a dry nitrogen atmosphere. The mixture was stirred and cooled to -70 ° and then a solution of 2,2,2-trichloroethyl (iS, 1 «S [or R], 6R, 7R) -3- (1 ^I -bromoethyl) -7- formamidoceph-3-em-4-carboxylate, 1-0xyd (250 mg, 0.52 mmol) in tetrahydrofuran (10 ml) at -70 to

309885 / U42

-75 ° added. After stirring at -70 ° for a further 21/4 hours, the mixture was hydrolyzed with saturated aqueous ammonium chloride solution (8 ml) and then partitioned between ethyl acetate (75 ml) and water (50 ml). The organic layer was washed with water (50 ml), dried and evaporated and passed through a silica gel column (Merck 0.05-0.2 mm). The appropriate fractions were combined, washed with aqueous sodium thiosulfate solution, dried and evaporated, the title compound remaining as a pale brown foam (65 mg, 0.135 mmol, 26%), ⁷ S ²⁷³ ' ⁵ (*)

Example 17

2,2,2-trichloroethyl (iS, 1'R [or S], 6R, 7R) -7-formamido-3- (1'-phenylethyl) -ceph-3-em-4-carboxylate, 1-oxide

In a manner similar to that described in the previous example, the 2,2,2-trichloroethyl (1S, 1 «R [or S], 6R, 7R) -3- (1'-bromoethyl) -7-formamidoceph-3-em -4-carboxylate, 1-oxide (1 g, 2.07 mmol) reacted with lithium diphenyl cuprate (2.0 equiv.), Whereby the title compound was obtained as a pale yellow foam (269 mg, 0.56 mmol, 28 #), λ. "272.5, 267.5 (turning point) nm (£ 10 170, 9680).

When speaking of "carbon acids" in the present application If, as indicated above, connections are made underneath of formula I understood. These are organic compounds that act as weak acids by creating a carbanion and release a proton.

309885 / U4

Claims (71)

'"/ ^ V ^ · patent claims 1·. Process for the preparation of a cephalosporin compound having an ethyl or substituted ethyl group in the 3-position, characterized in that a cephalosporin compound which in the 3-position is the basic group 3 - C -X t contains, wherein X is a halogen atom, and which contains no free amino or carboxyl groups, with a metal salt of a carbon acid with a pKa ^T .vert (determined in or estimated from a dilute aqueous solution at 25 ° C) of not less than 13 implements. 2. The method according to claim 1, characterized in that there is a compound of the cephalosporin starting material Basic formula (Ha) ζ 00R ^b used where R is a protected amino group, R mean a carbo-yl blocking group, X has the meaning given in claim 1, Z> S odor> S -> 0 means and the dashed lines between the 2-, 3- and 4-positions indicate that the connection is a Ceph-2-em- or Ceph-3-em isomer or a mixture thereof. 3. The method according to claim 2, characterized in that that X is a bromine atom. 309885/1 442 4. The method according to claim 2 or 3r, characterized in that that the metal salt of carbon acid is a compound of the formula R ¹ Lr ² (D is where M is a metal atom of valence η and 1 ? ^
R, R and R, the same or different can be, each a hydrogen atom or an organic group 12th or wherein two or more of the groups R, R and R- ^ together form a divalent or trivalent function and / or are bound together »bo that they are bound together with the Carbon atom form a cyclic structure, with any- »12 3 which of the remaining groups R, R or R is a hydrogen atom or represent an organic group. 5. The method according to claim 4, characterized in that M is an alkali metal atom. 6. The method according to claim 5, characterized in that 1-1 denotes a lithium atom. 7. The method according to any one of claims 4 to 6, characterized 12 ^ 5 characterized that R, R and R ^ each hydrogen, lower-alkyl, mean lower-alkenyl, alicyclic groups, aryl and / or aryl-lower-alkyl. 8. The method according to claim 7, characterized in that R is n-propyl and R and R ^ are each hydrogen. 9. The method according to any one of claims 4 to 6, characterized 12th
characterized that R and R together form a two-valued radio 309885 / U42 tion form and B? has the definition given in claim 7. 10. The method according to any one of claims 4 to 6, characterized 1 2
marked; that R and R together with the bound Carbon atom form a cyclic structure and R- ^{5 has} the definition given in claim 7. 11. The method according to claim 10, characterized in that 1 2 that R and R together with the adjacent bonded carbon atom a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring, the contains one or more heteroatoms such as oxygen, sulfur, nitrogen or / and phosphorus atoms. 12. The method according to claim 11, characterized in that 1 2 that R and R together with the bonded carbon atom form a dithianyl or dithiolanyl ring. 13. The method according to claim 12, characterized in that that R is a hydrogen atom, a methyl and / or a phenyl group means. 14. The method according to any one of claims 4 to 6, characterized 12 "3
characterized in that R, R and R ^ together with the bonded Carbon atom form a phenyl group. 15 · The method according to any one of claims 2 to 14, characterized characterized in that the reaction is carried out in the presence of a transition metal which forms an "ate" complex with the carbonic acid salt forms, is carried out. 16. The method according to claim 15, characterized in that the reaction in the presence of copper in the form of a Copper (I) salt is carried out. 309885 / U42 17. The method according to claim 15 or 16, characterized in that that a trialkylphosphine is added together with the source of the transition metal. 18. The method according to any one of claims 2 to 17, characterized in that R in the formula H is an acylamido group means containing one of the acyl groups (i) to (xvi) as previously defined, with the proviso that any Amino or carboxy substituents in such acyl groups are protected by substitution. 19. The method according to claim 18, characterized in that R ^{a is} formamido, phenylacetamido, phenoxyacetamido and / or thien-2-ylacetamido. 20. The method according to any one of claims 2 to 19, characterized characterized in that R is a carboxyl protecting group, wherein the ester group -COOR contains one of the groups (i) to (v) defined above. 21. The method according to claim 20, characterized in that R ^b 2; means. that R ^b 2,2,2-trichloroethyl, t-butyl and / or dipheny! methyl 22 .. The method according to claim 1, characterized in that the starting material used as a cephalosporin Connection of the basic formula (lib) R ^a J C00R ^b R ^C O ^ I.
Li Λ- ' 1· -I away
is wherein R, R ₁ X, Z and the dashed lines have the definitions given in claim 2, R ^{c denotes} a hydrogen atom or an organic group and R ^{e denotes} an organic group. 309885 / UA2 23. The method according to claim 22, characterized in that R ^{c is} a hydrogen atom or a lower alkyl group and R ^{e is} a lower alkyl group. 24. The method according to claim 23, characterized in that R ^{c is} a hydrogen atom and R ^{e is} a methyl group. 25. The method according to any one of claims 22 to 24, characterized characterized in that X represents a bromine atom. 26. The method according to any one of claims 22 to 25, characterized in that the metal salt of a carbon acid is used one as defined in claims 4-14 is used. 27. The method according to claim 26, characterized in that there is used as the metal salt of the carbon acid phenyllithium. 28. The method according to any one of claims 22 to 27, characterized in that the Urnetzung in the presence of a Transition metal, as it was defined in claims 15 to 17, is carried out. 29. The method according to any one of claims 22 to 28, characterized in that
Definition owns. characterized in that R ^a given in claim 18 30. The method according to claim 29, characterized in that R ^{a is} a forraamido group. 31. The method according to any one of claims 22 to 30, characterized in that R is the definition given in claim 20 owns. 32. The method according to claim 31, characterized in that R is a 2,2,2-trichloroethyl group. 309885 / UA2 33. A process for the preparation of compounds of the basic formula Ha, as defined in claim 2,. as described in Examples 1 to 15. 34. A process for the preparation of compounds of the basic formula Hb as defined in claim 22, as described in Examples 16 and 17. 35. 3-ethyl- and 3- (substituted-ethyl) -cephalosporins according to a method of claims 2 to 21 and 36. 3- (substituted-ethyl) -cephalosporins, produced by a process of claims 22 to 32 and according to claim 37. Connections of the basic formula (IVa) (R ^a ) 'an amino, protonated amino or acylamido group, (R) 'is a hydrogen atom or a carboxyl protecting group, Z / S or TS ^ O mean the dashed lines connecting the 2, 3 and 4 positions indicate that the connection is Ceph-2-em- or Ceph-3-ene isomers or mixtures thereof, and in what 4 5 6
R, R and R, the same or different can be, depending on lower-alkyl, lower-alkenyl, alicyclic, Aryl or aralkyl groups mean or in which two or more 309885 / U42 of the groups R, R and R together with the bonded carbon atom form a cyclic structure, any remaining groups R, R ⁵ or R being lower-alkyl, lower-alkenyl, alicyclic, aryl and / or aralkyl groups. '' 38. A compound according to claim 37 in the form of the Ceph-3-em isomers. 4th 39. A compound according to claim 37 or 38, wherein R and R ^ together with the bonded carbon atom a 5- or 6-membered carbocyclic ring or a 5- or 6-membered ring gene heterocyclic ring containing one or more heteroatoms such as oxygen, sulfur, nitrogen and / or phosphorus atoms contains, form and in which R is a lower-alkyl, lower-alkenyl, alicyclic, aryl or / and aralkyl group means. 40. Connection according to claim 39, characterized in that that R and R together with the bonded carbon atom form a dithianyl or dithiolanyl ring. 41. Compounds according to claim 40, characterized in that that R is a methyl or phenyl group. 42. Compounds according to claim 37 or 38, characterized in that that R, R and R together with the bonded carbon atom form a phenyl group. 43 · Compounds according to any one of claims 37 to 42, characterized in that (R ^a ) 'denotes an acyl amido group which contains one of the acyl groups (i) to (xvi) defined above. 44. Compounds according to any one of claims 37 to 42, characterized in that (R ^a ) 'is an amino, protonated amino, pormamido, phenoxyacetamide, thien-2-ylacetamido, 309885/1442 2-amino-2-phenylacetamido ~, 2- (t-butoxycarbonylamino) -2-phenylacetamido- and / or 2- (2,2,2-trichloroethoxycarbonylamino) -2-phenylacetamido group means. 45. Compounds according to any one of claims 37 to 44, characterized in that (R) 'denotes a carboxyl protective group and that the ester group -COO (R) ^! contains any of the groups (i) to (v) previously defined. 46. Compounds according to any one of claims 37 to 44, characterized in that (R) 'V / water, a 2,2,2-trichloroethyl, t-butyl and / or diphenylmethyl group. 47. 2,2,2-Trichloroethyl (6R, 7R) -3-benzyl-7 ■ -ormamidoceph-3-em-4-carboxylate and the 1S-0xyd of it. 48.2,2,2-trichloroethyl (6R, 7R) ^ - em-4-carboxylate hydrochloride and the 1S-oxide thereof. 49. 2,2,2-trichloroethyl (6R, 7R) -S-benzyl-1-phenoxyacetamidoceph-3-em-4-carboxylate and the 1S-0xyd of it. 50. (6R, 7R) ^ -Benzyl ^ -phenoxyacetamidaceph - ^ - enl · - ^ - carboxylic acid. 51. 2,2,2-Trichloroethyl (6R, 7R) -3-benzyl-7- (2'-thienylacetamido) -ceph-3-em-4-carboxylate and the 1S-0xyd of it. 52. (6R, 7R) -3-Benzyl-7- (2'-thienylacetamido) -ceph-3-em-4-carboxylic acid. 53. (2 «R, 6R, 7R) -7- (2'-aminophenylacetamido) -3-benzylc eph 3-em-4-carboxylic acid. 54. 2,2,2-trichloroethyl (2 'R, 6R, 7R) -3-benzyl-7- (2' - [2 », 2 ", 2" -trichloroethoxycarbonylamino] -phenylacetamido) -ceph-3-em-4-carboxylate and the 1S-0xyd of it. 309885 / UA2 55. t -Butyl (1S, 6R, 7R) -3- (2'-methyl-1S3'-dithiane-2 »-ylmethyl ) -7-phenoxyacetamidoceph-3-em-4-carboxylate, 1-oxide. 56. t-Butyl (6R, 7R) -7-phenoxyacetamido-3- (2'-phenyl-1 ^!, 3'-dithiolane-2 ^l -ylmethyl) -ceph-3-em-4-carboxylate and the 1S- Oxide of it. 57. (6R, 7R) -7-phenoxyacetamido-3- (2'-phenyl-1 ", 3 ^! -Dithiolan-2'-ylmethyl) -ceph-3-em-4-carboxylic acid. 58. Diphenylmethyl (1S, 6R, 7R) -7-formamido-3- (2 ^l -phenyl-1 ', 3'-dithiolan-2'-ylmethyl) -ceph ^ -em ^ -carboxylate-i-oxide. 59. t-Butyl (6R, 7R) -3-O ^r , 3'-dithiane-2 ¹ -ylmethyl) -7-phenoxyacetamidoceph-3-em-4-carboxylate and the 1S-oxide thereof. 60. (6R, 7R) -3- (1 ', 3'-dithian-2'-ylmethyl) -7-phenoxyacetamidoceph-3-em-4-carboxylic acid. 61. Diphenylmethyl (1S, 6R, 7R) -3- (1 ^!, 3'-dithiane-2. -Ylmethyl) 7-formamidoceph-3-em-4-carboxylate-1-oxide. 62. Connections of the basic formula T le b COO (R ^b ) ' ^RR vrorin (R ^a) ', (R ^b) ·, the dotted line, R ^L Z' ^r, R and R ⁶ are each hydrogen atoms or are as defined in claim 37 ^5, R ^c is a M ^T asserstoffatom or an organic group and R represent an organic group. 63. Compounds according to claim 62, characterized in that R ^{c is} a V / ass material atom or a lower alkyl group and R ^{e is} a lower alkyl group. 309885/1442 64. Compounds according to claim 63, characterized in that R ^{c is} a hydrogen atom and R ^{e is} a methyl group. 65. Compounds according to any one of claims 62 to 64, characterized in that they are in the form of the Ceph-3-em isomers are present. 66. Compounds according to any one of claims 62 to 65, characterized in that R, R and R together with the bonded Carbon atom represent a phenyl group. 67. Compounds according to any one of claims 62 to 66, characterized in that (R ^a ) 'has the meaning given in claim 43. 63. Compounds according to claim 67, characterized in that (R ^a ) 'denotes a formamido group. 69. Compounds according to any one of claims 62 to 68, characterized in that
Has meaning. characterized in that (R) 'the given in claim 45 70. A compound according to claim 69, characterized in that. (R ^b ) ^! Means 2,2,2-trichloroethyl. 71. 2,2,2-Trichloroethyl (iS, 1'R and S, 6R, 7R) -7-formamido-3- (i ^l -phenylethyl) -ceph-3-em-4-carboxylate-1-oxide. 309885/1442